Therapeutic agent



Patented Sept. 7, 1937 THERAPEUTIC AGENT Arthur L. Tatum, Madison, Wis.', assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application July 19, 1933,

Serial No. 681,227

1 Claim.

The invention relates to a new agent for human therapy and to the method of combating therewith. diseases caused by spirochetes and trypanosomes.

5 I have discovered that 3-amino-4-hydroxyphenylarsine oxide may be administered intravenously to human beings in such amounts as to have a highly beneficial spirochetocidal or trypanosomicidal action without toxic efl'ects.

I have further discovered that 3-amino-4- hydroxyphenylarsine oxide possesses a previously unsuspected and undemonstrated therapeutic utility' for clinical application and that the ratio of curative dose to the toxic dose is as high or higher than other well known and widely used arsenical. preparations such as arsphenamine and -neo-arsphenamine. I have demonstrated that 3-amino-4-hydroxyphenylarsine oxide may be used in human therapy and is a remarkable antisyphilitic agent. My invention therefore makes available for human therapy a remedial agent of great utility.

Prior to my invention and discovery, arsenical I preparations of 3-amino-4-hydroxyphenylarsine oxide have been discussed in the literature, but the concensus of opinion of all investigations has been that 3-amino-4-hydroxyphenylarsine oxide was too toxic for clinical use. My research in this field has demonstrated that despite the high toxicity, 3-amino-4-hydroxyphenylarsine oxide has a higher proportioned curative eifect and therefore a higher therapeutic eillciency. Animal experimentation carried out under my direction has shownthat the ratio between the minimal curative dose and the maximal tolerated dose is-at least as favorable and in many instances more favorable than the corresponding ratio of recognized arsenical preparations.

After obtaining the results of the laboratory experimentation, which confirmed my theories on the utility of 3-amino-4-hydroxyphenylarsine oxide, I made an extensive clinical investigation of 3-amino-4-hydroxyphenylarsin oxide and have demonstrated that when administered in the proper dosage it is of great utility in combating human syphilis and is relatively free from toxic reactions. Thus in spite of the generally accepted belief by those having intimate knowledge of arsenical therapy that 3-amino-4-hydroxyphenylarsine oxide was too toxic for human use,

I have proved the contrary that 3-amino-4- hydroxyphenylarsine oxide when properly administered is a therapeutic agent of great value for human therapy and has low toxicity compared with its curative efiect.

In obtaining the therapeutic agent of my inventlon'it is necessary to provide 3-amino-4- hydroxyphenylarsine oxide in pure form, free from undesirable contaminating substances and to associate the same with a carrier medium in 5 such form and such concentration as to be administered for human, therapy without toxic .reaction.

One method of obtaining this combination is to first obtain the hydrochloride of 3-amino-4- 10 hydroxyphenylarsine oxide as a solid stable substance of high purity. This compound may be represented by the following formula:

of a certain amount of sodium chloride, which is desirable for rendering the solution iso-tonic. Usually an additional amount of sodium chloride is required to be added to obtain this end. An 35 even more readily soluble mixture is obtained by incorporating sucrose in the dry mix in placeof having dry sodium chloride present. Furthermore, I- have found that the presence of this sucrose in the dry mix causes more of the ar- 4 senical 'to go into solution, thus providing the practical advantage of obtaining more concentrated solutions.

The exact amount of' the free base, 3-amino- 4-hydroxy-phenylarsine oxide, for producing a. 45 v dosage for intravenous injection into humans I may be varied within certain limits but I have found that 60 mg. is very satisfactory for producing curative -effects in human syphilis without toxic reaction. This can be compared to a dosage of from 600 to 900 mg. arsphenam'ine. The 60 mg. dose of 3-amino-4-hydroxy-phenylarsine oxide is preferably dissolved in 15 cc. of sterile water.

It is of course to be understood that the dosage may be varied with clinical conditions, but from the results so far obtained it seems desirable that in general the dose should range from 30 to 80 mg.

While amounts up to 120 mg. and above have proved to be well tolerated in many cases, the evidence so far has indicated that increasing the dose substantially above 60 mg. does not have a proportionately greater curative effect and therefore it does not appear that ordinary conditions call for individual doses of amounts substantially above 60 to 80 mg. It has been indicated clinically that 30 mg. doses have a positive action on spirochetes in lesions, and of course still smaller amounts may sometimes be found desirable.

Among the advantages of the use of 3-amino-4- hydroxy-phenylarsine oxide for human therapy are the following:

1-3-amino-4-hydroxy-phenylarsine oxidemay be chemically assayed audits emcacy determined independently of physiological tests. This is in contradistinction to the well known arsenicals which require physiological assay.

2-3-amino-4-hydroxy-pheny1arsine oxide does not become more toxic through decomposition. Exposure to air tends to diminish the toxicity.

33-amino 4-hydroxy-phenylarsine oxide may be compounded in such form as to permit its administration by simple solution in sterile water.

poules as a mixture of solid substances containing the hydrochloride of 3-amino-4-hydroxyphenylarsine oxide together with sodium carbonate or other neutralizing agent in an amount just suilicient to obtain a neutral solution.

4-3-amino-4-hydroxy-phenylarsine oxide is administered in much smaller quantities than other arsenical preparations, thus introducing 4o muchsmaller amounts of metallic arsenic and reducing the chance for arsenical poisoning.

As a result of my research the following data relative to the effect of 3-amino-4-hydroxyphenylarsine oxide on experimental animals has This may be done by supplying the drug in ammgm./kgm. body weight; The maximal tolerated I close is 12 mgm./kgm. body weight.

5- In 24-hour infections of T. equiperdum in the rat, 3-amino-4-hydroxy-phenylarsine oxide cures in doses of 0.8 mgliL/kgm. body weight. The therapeutic index is 25.

6-In 24-hour infections of T-rhodesiense in the rat, 3-amino-4-hydroxy-phenylarsine oxide cures in doses of 9 mgm./kgm. body weight. The therapeutic index is 2.2.

7One milligram per kilogram of 3-amino-4- hydroxy-phenylarsine oxide will prevent infection withTreponema pallidum in the rabbit when used four days, or less, after the inoculation.

8-A single dose of six milligrams per kilogram of 3-amino-4-hydroxy-phenylarsine oxide will cure the rabbit of syphilis after the lesions have developed. The therapeutic index is 1.66. Tests carried out under similar conditions with neoarsphenamine have indicated a therapeutic index of 1.1.

9-0.8 milligram per kilogram of 3-amino-4- hydroxy-phenylarsine oxide when used once a week for three weekscures rabbit syphilis. The index is 12.5. One brand of neo-arsphenamine used under the same conditions has an index of 5, another 10.

Clinical investigation has indicated the following evidence regarding the eflect of 3-amino- 4-hydroxy-phenylarsine oxide in human therapy:

1-Spirochetes in open lesions have disappeared on the average in less than 24 hours.

2Healing of visible lesions has been rapid and complete and equal to that by arsphenamine. .3-The Wassermann reaction has been reversed to negative ina high percentage of patients with early syphilis.

4-Ocular damage, neuritis and exfoliative dermatitis have not been observed.

5-Venous sclerosis is uncommon.

6The Herxheimer reaction usually is mild or absent after a small initial dose.

7Nitritoid reactions do not occur.

From the data herein set forth it will be ob served that my inventionhas made available for human therapy a therapeutic agent having heretofore unsuspected beneficial properties. While I have referred in the specification to a preferred embodiment of the invention, it is to be understood that the scope of the invention is to be determined by the claim appended hereto.

What I claim as my invention isz A spirocheticidal preparation for use in suitable concentration for the purpose of destroying spirochetes harbored in the human body without harming the human, comprising stable 3-amino- 4-hydroxy phenylarsine oxide hydrochloride in pure solid form free from undesirable contaminants.

ARTHUR L. TATUM. 

